Efficacy of antiretroviral therapy (ARV) in HIV-1 infected individuals is determined by viral suppression and restoration of CD4 +T cell numbers in the peripheral blood, which represents only 2% of the total lymphocytes in the body; whereas, the gut associated lymphoid tissue (GALT) harbors >90% of the lymphocytes. The kinetics of CD4 +T cell restoration and function in GALT following ARV has not been fully determined. Our preliminary results showed a modest but incomplete restoration and function of intestinal CD4+T cells in SIV-infected animals during therapy. We propose that the alterations in composition of intestinal T lymphocyte subsets (increased prevalence of CD8+ T cells and inflammatory cytokines such as TNFalpha subsequent to CD4+ T cell depletion in primary SIV infection may have a negative impact on the restoration of intestinal CD4 +T cells during ARV. Immune activation and inflammatory cytokines such as TNFalpha may contribute to the delay in the CD4 + T cell restoration. The overall objective of this application is to develop strategies to improve or accelerate CD4 +T cell restoration in GALT during HIV infection and to identify potential mechanisms of CD4 + T cell repopulation by using the SIV-infected rhesus macaque model. There are three specific aims. (1) To determine the effects of TNFalpha inhibitor, RDP58, on intestinal CD4+ T cell restoration and function, T cell homeostasis, cell cycle stage and viral suppression in SIV-infected rhesus macaques during PMPA antiviral therapy. Therapy will be initiated in the primary or chronic stage of viral infection and longitudinal jejunal biopsy and peripheral blood samples analyzed for CD4+ T cell repopulation and function, changes in cell cycle and levels of apoptosis, viral suppression and evolution of genomic diversity. (2) To determine the effect of CD8 vT cell depletion on repopulation and function of CD4 + T cell subsets and intestinal T cell homeostasis and viral suppression and decay kinetics and genomic diversity in GALT of SIV-infected rhesus macaques receiving therapy. This study will examine the contribution of CD8+ T cells in killing of productively infected cells in SIV infected macaques during potent antiretroviral therapy. (3) To examine the progression of SIV-induced intestinal CD4+T cell depletion and CD4+ T cell restoration during therapy by gene expression analysis. Examination of gene expression profiles in GALT of SIV-infected animals with and without therapy will detect cellular and molecular mechanisms involved in the infection associated pathophysiologic process. The proposed studies may provide insights into mechanisms of CD4+T cell depletion during SIV infection and subsequent CD4+ T cell restoration in GALT following ARV in combination with an immunomodulator or CD8+ T cell depletion.